Cinnamaldehyde, cinnamic acid, and cinnamyl alcohol, the bioactives of Cinnamomum cassia exhibit HDAC8 inhibitory activity: An In vitro and In silico study

Abstract

Background:The altered expression of histone deacetylase family member 8 (HDAC8) has been found to be linked with various cancers, thereby making its selective inhibition a potential strategy in cancer therapy. Recently, plant secondary metabolites, particularly phenolic compounds, have been shown to possess HDAC inhibitory activity.Objective:In the present work, we have evaluated the potential of cinnamaldehyde (CAL), cinnamic acid (CA), and cinnamyl alcohol (CALC) (bioactives of Cinnamomum) as well as aqueous cinnamon extract (ACE), to inhibit HDAC8 activity in vitro and in silico.Materials and Methods:HDAC8 inhibitory activity of ACE and cinnamon bioactives was determined in vitro using HDAC8 inhibitor screening kit. Trichostatin A (TSA), a well-known anti-cancer agent and HDAC inhibitor, was used as a positive control. In silico studies included molecular descriptor Analysis molecular docking absorption, distribution, metabolism, excretion, and toxicity prediction, density function theory calculation and synthetic accessibility program.Results:Pharmacoinformatics studies implicated that ACE and its Bioactives (CAL, CA, and CALC) exhibited comparable activity with that of TSA. The highest occupied molecular orbitals and lowest unoccupied molecular orbitals along with binding energy of cinnamon bioactives were comparable with that of TSA. Molecular docking results suggested that all the ligands maintained two hydrogen bond interactions within the active site of HDAC8. Finally, the synthetic accessibility values showed that cinnamon bioactives were easy to synthesize compared to TSA.Conclusion:It was evident from both the experimental and computational data that cinnamon bioactives exhibited significant HDAC8 inhibitory activity, thereby suggesting their potential therapeutic implications against cancer.SUMMARY Pharmacoinformatics studies revealed that cinnamon bioactives bound to the active site of HDAC8 enzyme in a way similar to that of TSAThe molecular descriptors of cinnamon compounds successfully correlated with TSA values. The binding interactions and energies were also found to be close to TSASynthetic accessibility values showed that cinnamon bioactives were easy to synthesize compared to TSA. Abbreviations used: ACE: Aqueous Cinnamon Extract; DFT: Density Function Theory; CAL: Cinnamaldehyde; CA: Cinnamic Acid; CALC: Cinnamyl Alcohol; MW: Molecular Weight; ROTBs: Rotatable Bonds; ROF: Lipinski's Rule of Five; TSA: Trichostatin A; PDB: Protein Data Bank; RMSD: Root Mean Square Deviation; HBA: Hydrogen Bond Acceptor; HBD: Hydrogen Bond Donor; ADMET: Absorption, Distribution, Metabolism, Excretion and Toxicity; FO: Frontier Orbital; HOMOs: Highest Occupied Molecular Orbitals; LUMOs: Lowest Unoccupied Molecular Orbitals; BE: Binding Energy.

Cinnamomum cassia Presl: A Review of Its Traditional Uses, Phytochemistry, Pharmacology and Toxicology

“…Moreover the bioactive components of C. cassia were easier to synthesize. These studies showed that C. cassia is a potential antitumor drug [58]. C. cassia components have been extensively studied in lung cancer, breast cancer, oral cancer, cervical cancer, head and neck squamous cell carcinoma.…”

Trans-Cinnamaldehyde Inhibitory Activity Against <i>mrkA</i>, <i>treC</i>, and <i>luxS</i> Genes in Biofilm-forming <i>Klebsiella pneumoniae</i>: An In Silico Study

“…28 Besides having anti-biofilm and antibacterial activity, cinnamaldehyde has been shown to have anticancer effect. 29 Cinnamon bioactive compounds have shown significant Histone deacetylases 8 (HDAC8) inhibitory activity suggesting their potential therapeutic applications in cancer therapy. 30 Inhibitors of biofilm formation with strong antihelminthic effects include 4-bromo and 4-chloro cinnamaldehydes, methyl and trans-4-methyl cinnamaldehydes.…”

“…30 Inhibitors of biofilm formation with strong antihelminthic effects include 4-bromo and 4-chloro cinnamaldehydes, methyl and trans-4-methyl cinnamaldehydes. 29 Cinnamaldehyde showed fungicidal activity through a mechanism of action likely related to ergosterol complexation. 31 Major components of essential oils of cinnamon have been identified by molecular docking study as potential inhibitors of hemolysin, phospholipase, and biofilm formation in Candida spp.…”

Aqueous Extract of Cinnamon (Cinnamomum spp.): Role in Cancer and Inflammation

“…In an in vitro and in silico study, aqueous extract of cinnamon, cinnamic acid, cinnamyl alcohol, and cinnamaldehyde, were all shown to bind to the HDAC8 enzyme. The whole extract was much more efficient in inhibiting the enzyme compared to purified components [ 76 ]. Transformed cancerous cells are associated with increased activity of 26S proteasome, the protein degrading machinery.…”